The development of highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality in HIV-infected patients, yet the regimen also often results in chronic metabolic diseases. Dyslipidemia, insulin resistance, and lipodystrophy observed in patients receiving HAART have been linked to HIV protease inhibitors (PI). Previous studies have shown that HIV Pis activate ER stress, which underlies inflammatory responses and dysregulation of lipid metabolism in macrophages and hepatocytes. Within adipocytes, key players in both body lipid storage and inflammation, HIV Pis have been shown to activate ER stress, increase proinflammatory cytokine secretions, alter lipid metabolism, and inhibit differentiation of pre-adipocytes to mature adipocytes. Yet, the cellular mechanisms of HIV Pl-induced dysregulations have not been elucidated. We hypothesize that HIV Pis disrupt lipid metabolism by activating ER stress and inflammatory responses in adipocytes. We will test this hypothesise through three specific aims. AIM 1 is to elucidate the mechanism of HIV Pl-induced ER stress in adipocytes. We will accomplish this by studying protein and mRNA level changes in pre- and differentiated murine, as well as human, cultured adipocytes. AIM 2 is to define the role of ER stress in HIV Pl-induced dysregulation of adipocyte lipid metabolism and induction of the inflammatory response. We will first focus on the effects of HIV Pis in these processes and then knock down key players of the ER stress pathway to test how these effects are altered. Aim 3 is to characterize the contribution of HIV Pl-induced macrophage cytokine secretions play in adipocyte ER stress activation, adipocyte cytokine secretion, and adipose tissue inflammation. We will treat co-cultures of macrophages and adipocytes to analyze differences in UPR activation and cytokine secretions versus cells cultured and treated alone. We will follow this by in vitro studies to determine the extent HIV PI treatment has on adipose tissue inflammation. By understanding how HIV Pis disrupt normal function in key cells of metabolic disease, we can learn to prevent the onset of these diseases by using concurrent alternative therapies with HAART in HIV patients. Public Health Relevance: HAART-induced dylipidemia and lipodystrophy are two major side effects of a pivotal drug regimen used for treating HIV-infected patients. Determining the underlying cellular/molecular mechanisms by which some of these drugs cause devastating metabolic diseases can allow us to develop new therapies that will counteract induction of these chronic illnesses.